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【结 构 式】 
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【分子编号】61529 【品名】(6R,7R)-7-amino-3-{[4-(1-methyl-4-pyridiniumyl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 【CA登记号】 |
【 分 子 式 】C16H14N4O3S3 【 分 子 量 】406.51032 【元素组成】C 47.27% H 3.47% N 13.78% O 11.81% S 23.66% |
合成路线1
该中间体在本合成路线中的序号：(IX)The bromination of 4-acetylpyridine (I) with Br2 and HBr in acetic acid gives 4-bromoacetylpyridine (II), which is cyclized with ammonium dithiocarbamate (III) and NaOMe to yield the thiazole (IV). The condensation of the sodium salt (IV) with the cephalosporanic ester (V) in THF affords the adduct (VI), which is treated with methyl iodide to provide the pyridinium salt (VII). The deprotection of (VII) with PCl5 and pyridine gives the aminocephalosporanic derivative (VIII), which is treated with TFA and anisole, yielding the inner salt (IX). Finally, this compound is condensed with the acid chloride (X) by means of NaHCO3 in THF/water to afford the target cephalosporin.
| 【1】 Ishikawa, T.; Matsunaga, N.; Tawada, H.; et al.; TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: Synthesis, physicochemical and pharmacological properties. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-332. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 59510 | 4-Acetylpyridine; Methyl 4-pyridyl ketone | 1122-54-9 | C7H7NO | 详情 | 详情 |
| (II) | 61522 | 2-bromo-1-(4-pyridinyl)-1-ethanone | C7H6BrNO | 详情 | 详情 | |
| (III) | 61523 | amino(aminosulfanyl)thioxomethane | CH4N2S2 | 详情 | 详情 | |
| (IV) | 61524 | C8H5N2NaS2 | 详情 | 详情 | ||
| (V) | 61525 | 4-methoxybenzyl (6R,7R)-7-[(ethoxycarbonyl)amino]-8-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H19F3N2O9S2 | 详情 | 详情 | |
| (VI) | 61526 | 4-methoxybenzyl (6R,7R)-7-[(ethoxycarbonyl)amino]-8-oxo-3-{[4-(4-pyridinyl)-1,3-thiazol-2-yl]sulfanyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H24N4O6S3 | 详情 | 详情 | |
| (VII) | 61527 | 4-{2-[((6R,7R)-7-[(ethoxycarbonyl)amino]-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)sulfanyl]-1,3-thiazol-4-yl}-1-methylpyridinium iodide | C27H27IN4O6S3 | 详情 | 详情 | |
| (VIII) | 61528 | 4-{2-[((6R,7R)-7-amino-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)sulfanyl]-1,3-thiazol-4-yl}-1-methylpyridinium chloride | C24H23ClN4O4S3 | 详情 | 详情 | |
| (IX) | 61529 | (6R,7R)-7-amino-3-{[4-(1-methyl-4-pyridiniumyl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H14N4O3S3 | 详情 | 详情 | |
| (X) | 31455 | 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride | C6H7ClN4O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The bromination of 4-acetylpyridine (I) with Br2 and HBr in acetic acid gives 4-bromoacetylpyridine (II), which is cyclized with ammonium dithiocarbamate (III) and NaOMe to yield the thiazole (IV). The condensation of the sodium salt (IV) with the cephalosporanic ester (V) in THF affords the adduct (VI), which is treated with methyl iodide to provide the pyridinium salt (VII). The deprotection of (VII) with PCl5 and pyridine gives the aminocephalosporanic derivative (VIII), which is treated with TFA and anisole yielding the inner salt (IX). The reaction of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetic acid (X) with PCl5 in ethyl acetate affords the 2-[5-dichlorophosphorylamino)-1,2,4-thiadiazol-3-yl]-2-(ethoxyimino)acetyl chloride (XI), which is finally condensed with the aminocephalosporanic acid (IX) by means of NaOAc and further hydrolyzed in acidic medium to provide the target phosphorylated cephalosporin.
| 【1】 Ishikawa, T.; Matsunaga, N.; Tawada, H.; et al.; TAK-599, a novel N-phosphono type prodrug of anti-MRSA cephalosporin T-91825: Synthesis, physicochemical and pharmacological properties. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-332. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 59510 | 4-Acetylpyridine; Methyl 4-pyridyl ketone | 1122-54-9 | C7H7NO | 详情 | 详情 |
| (II) | 61522 | 2-bromo-1-(4-pyridinyl)-1-ethanone | C7H6BrNO | 详情 | 详情 | |
| (III) | 61523 | amino(aminosulfanyl)thioxomethane | CH4N2S2 | 详情 | 详情 | |
| (IV) | 61524 | C8H5N2NaS2 | 详情 | 详情 | ||
| (V) | 61525 | 4-methoxybenzyl (6R,7R)-7-[(ethoxycarbonyl)amino]-8-oxo-3-{[(trifluoromethyl)sulfonyl]oxy}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C19H19F3N2O9S2 | 详情 | 详情 | |
| (VI) | 61526 | 4-methoxybenzyl (6R,7R)-7-[(ethoxycarbonyl)amino]-8-oxo-3-{[4-(4-pyridinyl)-1,3-thiazol-2-yl]sulfanyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C26H24N4O6S3 | 详情 | 详情 | |
| (VII) | 61527 | 4-{2-[((6R,7R)-7-[(ethoxycarbonyl)amino]-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)sulfanyl]-1,3-thiazol-4-yl}-1-methylpyridinium iodide | C27H27IN4O6S3 | 详情 | 详情 | |
| (VIII) | 61528 | 4-{2-[((6R,7R)-7-amino-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)sulfanyl]-1,3-thiazol-4-yl}-1-methylpyridinium chloride | C24H23ClN4O4S3 | 详情 | 详情 | |
| (IX) | 61529 | (6R,7R)-7-amino-3-{[4-(1-methyl-4-pyridiniumyl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate | C16H14N4O3S3 | 详情 | 详情 | |
| (X) | 31455 | 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride | C6H7ClN4O2S | 详情 | 详情 | |
| (XI) | 61530 | 2-{5-[(dichlorophosphoryl)amino]-1,2,4-thiadiazol-3-yl}-2-(ethoxyimino)acetyl chloride | C6H6Cl3N4O3PS | 详情 | 详情 |